If the mutation is limited to just one copy of the HBB gene, carriers can lead a relatively normal life. “A person with a single mutation will have great difficulty becoming a professional athlete, but they will still be able to go jogging, swimming, and cycling,” says Boontanrart, who herself is a carrier of a mutated gene. But if both copies are damaged, the situation becomes problematic: “If you’re planning to have children with a partner who also has the mutation, the children might inherit both mutated genes – one from the father, the other from the mother. These children would have a serious illness.”
Increasing delta globin production
An effective treatment for beta-hemoglobinopathies is yet to be available. In her new study, Boontanrart and her colleagues show that the problem could be solved by increasing production of delta globin, which would replace the faulty beta globin. “Humans naturally produce only tiny amounts of delta globins. This is linked to a special DNA control sequence that hinders the transcription of the relevant gene,” Boontanrart says. So the researchers hit upon the idea of altering this control sequence in order to increase delta globin production.
Here, Boontanrart used the CRISPR-Cas9 gene scissors to alter the DNA of progenitor blood cells by inserting three additional sections ahead of the HBD gene, which contains the blueprint for delta globins. These insertions are designed to stimulate the cell machinery to produce more delta globin – and that’s exactly what happened.
The results are promising: “We managed to significantly increase in the proportion of delta globin, to the point where it could offer a therapeutic benefit,” Boontanrart says.
However, inserting multiple DNA elements is still not without its challenges. “It’s more demanding than the techniques used by other research groups and pharmaceutical companies,” Boontanrart says. Researchers in the US are also using the CRISPR-Cas9 system to tackle beta haemoglobinopathies by manipulating blood stem cells to produce fetal haemoglobin. This is the predominant type of haemoglobin found in fetuses, but babies stop producing it at the latest when they are a few months old. For their proposed treatment, the US researchers plan to use fetal haemoglobin to replace beta globin. This approach is currently being vetted for approval by the Federal Drug Administration (FDA).